Preparation of i



UNITED STAT ES.

PREPARATIONOF 1,2,3-SUBSTITUTED PYRAZOLONE DERIVATIVES Jules Henri 'Theophile 'Ledrut, Brussels, Belgium, assignor to Heyden- Pharmacal Company, New York, N. Y., a corporation of Delaware TENT OFFICE;

NoDfrawing. Application January-10, 1949; Se-' rial'No. 70,153. In Belgium January 10, 1948 9 Claims, (Cl. 260-310) 2 Myinventionrelates-to the preparation of 1; 2, may use, for example, l-phenyl-2,3dimethyl4- 3 substituted pyrazolone-aldehydes and the prod- (fl,fi,B-trichloro (or tribromo) -aehydroxyethyl-) uctsobtainedthereby. S-pyrazolone. In this case the following reaction The object of my invention is toob-tain prodtakes place: nets of the above character in an advantageous 5 CHPO manner. I m0 0 This invention is concerned witha method of CHPB 0:0 preparing 1,2,3-substituted pyrazoline aldehydes N having the general formula (HHS CH'Cl: 0H=-c'=( 3'--cHo CHaN 01:0. 21 5 R'N =0 I \IET/ 3 t The 1-phenyl-2,3-dimethyl-4-({3,/8,Btrichlor0 I H a-hydroxyethyl) -5-pyrazolone used in the above m which and R represent respectlvely' reaction may be obtained by heating ,l-phenyl- M aiyl'gmups and the Products thus 2,3-dimethyl-5-pyrazolone With chloral hydrate tamedas has been described in the literature by Behal According to the process a 1,2,3-subst1tuted and Choay (Ann Phys. Chim" 1892, XXXIX, derivati f 6 54 320) and Krey (These Ina, 1892, p. 32).

ethyl) -5-pyrazolone having the general formula These compounds, the preparation of which R- =CCHOR"-CHa has been referred to above, as well as certain of l; =0 their derivatives as hereinafter referred to, have been found to possess valuable therapeutic properties. For example, antipyrine-l-aldeh'yde (1-pheny1-2,3-dimethyl-5-pyrazolone aldehyde) inWhichRR', and R are, respectively, alkyl or is approximately three times as effective as an" aryl groups, R a bromine or chlorine atom, pif etic as is aatipv i and un a hydrogen t or a acyl group, may While my 1nvent1on is capable of being carried be decomposed by being heated to its boiling point out 111 many dlfferent Ways the purpose of in thexpresen-ce of potassium carbonate or any illustration I have described hereinafter only other. similar alkaliso as to yield a. 1,2,3-substicertailn p S thereoftuted pyrazolone aldehyde having the formula m I mayproceed as follows the O parts mentioned being parts by weight: RN =0 Example I f Ten parts of 1-p-tolyl-2,3edimethyl-5epyrazolone. is added to nine parts of chloral hydrate,

and the mixture is then heated in an oil bath at The expresslon R a'oxyethyl refers tome 120 C. for about three hours. When cool the groupresulting solid product is washed three times by l i slurrying it with boiling water. It is then recrys- -'c;-otallized from ethyl alcohol. The yield obtained is ,1, I 13.5 parts of 1-p tolyle2,3-dimethyl-4-(5,5, 3-

fim, tri-chloro-a-hydroxyethyl) -5-pyrazolone, having a melting point of 1'9l-192 C. This product conin which R""-is connected to an oxygen atom tains 30.40% Cl (theoretical amount 30-42%). which is in turn connected to the a. carbon atom To 300 parts of a boiling, concentrated water of an ethyl group. When R" is hydrogen, the solution of potassium carbonate is then slowly expression may be written a-hydroxyethyl and added 3.5 parts of 1-p-to1yl-2,3-dimethyl-4- when R is acetyl, the expression may be written (dflfi-tric'hloro-aehydroxyethyl) 5 pyrazolone.

as e-acetoxyethyl. This mixture is held at the boiling point and As the 1,2,3-substituted derivative of 4-(fififishaken. until the evolution ofchloroformehas trihalogen-R""- oxyethyD-i pyrazolone, one fiaceased. The yield is 23 parts of 1-p-tolyl-2,3-

A mixture of 2,2 parts of 1,3-diphenyl-2- methyl--pyrazolone and 1.45 parts of chloral hydrate'is heated in an oil bath at 135 C. On cooling the resulting product is washed several times with boiling water and then recrystallized from ethyl alcohol. The yield is 2.6 parts of 1,3-diphenyl 2 methyl-4-(sfip-trichloro-a-hydroxyethyl) -5-pyrazolone, which has a melting point of 188 C. The product contained 27.1% C1 (theoretical amount-26.8

Fifty-five parts of 1,3-diphenyl-2-methyl-4- (Amp-trichloro-a-hydroxyethyl)-5-pyrazolone is then mixed with 400 parts of a saturated potassium carbonate water solution, and th mixture is boiled and agitated until substantially all of the chloroform has been given off. The yield is 37 parts of crude product. After recrystallization the 1,3-diphenyl-2-methyl-5-pyrazolone aldehyde obtained is a yellow crystalline substance melting at 158-159 C.

Example III One hundred parts of 1-phenyl-2,3-dimethyl- 4 (Bflfi-trichloro-a-hydroxyethyl) -5-pyrazolone is poured slowly into 260 parts of a cold, saturated potassium carbonate water solution. The mixture is then boiled and shaken vigorously until chloroform is no longer given off. The yield of crude material after washing with ice water and drying is approximately 95% of the theoreti-- cal amount. The 1 phenyl-2,3 dimethyl-5- pyrazolone aldehyde is recrystallized from dioxane and from a mixture containing equal parts of ethyl alcohol and ethyl acetate. The product melts at approximately 160 C. It is soluble in water, alcohol, dioxane, ethyl acetate, and slightly soluble in chloroform, ether, and benzene. Its oxime derivative melts at 220 0., Whereas the phenyl hydrazone derivative has a melting point of 255 C.

Example IV Example V To a cold saturated potassium carbonate water solution is added 1 phenyl 2,3 dimethyl 4- (fi, 3,,8 tribromo-a-hydroxyethyl)-5-pyrazo1one. The mixture is boiled and shaken vigorously until all of the bromoform has been given OK. The product is washed with ice water, dried, and then recrystallized from dioxane.

- Example VI Bromal hydrate is reacted in molecular proportions with l-phenyl-2,3-dimethyl-5-pyrazolone by heating at 50 C. for one to two hours. The 1-phenyl-2,3-dimethyl-4-( 8,,8,;3-tribromo-ahydroxyethyl)-5-pyrazolone formed is purified by recrystallization from ethyl ether. This compound is then treated with a potassium carbonate water solution as described above to yield the corresponding desired pyrazolone aldehyde.

While I have described my invention above in detail it will be understood that many changes may be made therein, as to the proportions, temperature, etc., without departing from the spirit of my invention. For instance, in place of a potassium carbonate water solution used in the above examples I may use a water solution in any desired proportions of potassium carbonate and potassium hydroxide, for example containing equal parts of potassium carbonate and potassium hydroxide, to decompose the 1,2,3-trisubstituted-4- (5,3,5-trihalogen-hydroxyethyl)-5-pyrazolone or the 1,2,3-trisubstituted-4-(pflfi-trihalogen acetoxyethyl) -5-pyrazolone. The presence of KOH tends to increase the rate of reaction. Or, instead, potassium hydroxide, for example a 10% water solution, may be used alone, but in this case the resultantproduct is not entirely pure, and the yields are lower than those obtained when potassium carbonate alone is used.

I claim: I g

l. A process for preparing 1,3-diphenyl-2- methyl-S-pyrazolone aldehyde which comprises reacting a 1,2,3-substituted derivative of 4413,5 8- trihalogen-a-R -oxyethyl) -5 -pyrazolone having the general formula wherein R and R are phenyl groups, R is a methyl group, R is a chlorine atom, and R"" is a member selected from the group consisting of hydrogen and acetyl, with an aqueous solution of potassium carbonate.

3. A process for preparing 1,3-diphenyl-2 methyl-5-pyrazolone aldehyde which comprises reacting a 1,2,3-substituted derivative of 4-(;8,;8,;8 trihalogen-a-R'"'-oxyethy1) -5-pyrazo1one having the general formula RC=COHOR-C R;

wherein R and R" are phenyl groups, R is a methyl group, R' is a bromine atom, and R'- is a member selected from the group consisting of hydrogen and acetyl, with an aqueous solution of potassium carbonate.

4. A process for preparing 1,3diphenyl-2- methyl-5-pyrazolone aldehyde which comprises reacting a 1,2,3-substituted derivative of 44 8,5 8-

trihalogen-a-R. -oxyethyl) -5-pyrazolone having the general formula RC=CCHO RC R:

wherein R and R" are phenyl groups, R is a methyl group, R is a bromine atom, and R"" is hydrogen, with an aqueous solution of potassium carbonate.

6. A process for preparing 1,3-diphenyl-2- methyl-5-pyrazolone aldehyde which comprises reacting a 1,2,3-substituted derivative of 4-(B,,3,B- trihalogen-a-R '-oxyethyl) -5-pyrazo1one having the general formula wherein R and R" are phenyl groups, R is a methyl group, R' is a chlorine atom, and R" is an acetyl radical, with an aqueous solution of potassium carbonate. 7

7. A 'process for preparing 1,3-diphenyl-2- methyI-S-pyrazolone aldehyde which comprises reacting a 1,2,3-substituted derivative of 445,549 trihalogen-a-R '-oxyethyl)-5-pyrazolone having the general formula wherein R and R" are phenyl groups, R is a methyl group, R is a bromine atom, and R"" is an acetyl radical, with an aqueous solution of potassium carbonate.

8. A process for preparing 1,3-diphenyl-2- methyl-5-pyrazolone aldehyde which comprises reacting a 1,2,3-substituted derivative of 44/535,5- trihalogen-a-R'"-oxyethyl) -5-pyrazolone having the general formula ill wherein R and R are phenyl groups, R is a methyl group, R is a chlorine atom, and R"" is hydrogen, with an aqueous solution of potassium carbonate, and then recrystallizing the reaction product thus formed to obtain 1,3- diphenyl-2-methyl-5-pyrazolone aldehyde in the form of a yellow crystalline material.

9. 1,3-diphenyl-2-methy1-5-pyrazolone hyde.

alde- JULES HENRI THEOPHILE LEDRUT.

REFERENCES CITED The following references are of recordin the file of this patent:

Passerini, Gazz. Chim. Ital., vol. 69, pp. 658 to 664 (1939).

Ridi, Gazz. Chim. Ital., 71 pp. 106-111, (1941) Ridi, Gazz. Chim. Ital., vol. '77, pp. 3 to 12 (1947) 

1. A PROCESS FOR PREPARING 1,3-DIPHENYL-2METHYL-5-PYRAZOLONE ALDEHYDE WHICH COMPRISES REACTING A 1,2,3-SUBSTITUTED DERIVATIVE OF 4-(B,B,BTRIHALOGEN-A-R""-OXYETHYL)-5-PYRAZOLONE HAVING THE GENERAL FORMULA WHEREIN R AND R" ARE PHENYL GROUPS, R'' IS A METHYL GROUP, R"'' IS A HAOLGEN ATOM, AND R"" IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND ACETYL, WITH AN INORGANIC ALKALI,
 9. 1,3-DIPHENYL-2-METHYL-5-PYRAZOLONE ALDEHYDE. 